Cyclic sulfamides for inhibiton of gamma-secretase

ABSTRACT

Compounds of formula I:  
                 
inhibit the processing of AP by gamma-secretase, and hence are useful for treatment or prevention of Alzheimer&#39;s disease.

The present invention relates to a novel class of compounds, theirsalts, pharmaceutical compositions comprising them, processes for makingthem and their use in therapy of the human body. In particular, theinvention relates to novel sulfamide derivatives which modulate theprocessing of APP by γ-secretase, and hence are useful in the treatmentor prevention of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia.Although primarily a disease of the elderly, affecting up to 10% of thepopulation over the age of 65, AD also affects significant numbers ofyounger patients with a genetic predisposition. It is aneurodegenerative disorder, clinically characterized by progressive lossof memory and cognitive function, and pathologically characterized bythe deposition of extracellular proteinaceous plaques in the corticaland associative brain regions of sufferers. These plaques mainlycomprise fibrillar aggregates of β-amyloid peptide (Aβ). The role ofsecretases, including the putative γ-secretase, in the processing ofamyloid precursor protein (APP) to form Aβ is well documented in theliterature and is reviewed, for example, in WO 01/70677.

There are relatively few reports in the literature of compounds withinhibitory activity towards γ-secretase, as measured in cell-basedassays. These are reviewed in WO 01/70677. Many of the relevantcompounds are peptides or peptide derivatives.

WO 01/70677 and WO 02/36555 disclose, respectively, sulfonamido- andsulfamido-substituted bridged bicycloalkyl derivatives which arebelieved to be useful in the treatment of Alzheimer's disease, but donot disclose or suggest compounds in accordance with the presentinvention.

The present invention provides a novel class of bridged bicycloalkylsulfamide derivatives which show a particularly strong inhibition of theprocessing of APP by the putative γ-secretase, and thus are useful inthe treatment or prevention of AD.

According to the invention there is provided a compound of formula I:

wherein the pyrazole group is attached at one of the positions indicatedby an asterisk and X is attached at a position adjacent thereto;

X represents H, OH, C₁₋₄alkoxy, Cl or F;

Ar represents phenyl or 6-membered heteroaryl, either of which bears 0-3substituents independently selected from halogen, CF₃, CHF₂, CH₂F, NO₂,CN, OCF₃, C₁₋₆alkyl and C₁₋₆alkoxy;

R¹ represents a hydrocarbon group of 1-5 carbon atoms which isoptionally substituted with up to 3 halogen atoms; and

R² represents H or a hydrocarbon group of 1-10 carbon atoms which isoptionally substituted with up to 7 halogen atoms;

provided that when X is H, R² does not represent 2,2,2-trifluoroethyl;or a pharmaceutically acceptable salt thereof.

In a subset of the compounds of formula I, R² represents H or ahydrocarbon group of 1-10 carbon atoms which is optionally substitutedwith up to 3 halogen atoms.

It will be readily apparent to those skilled in the art that anycompound in accordance with formula I may exist in two enantiomericforms, depending on which of the ring positions indicated by an asteriskis bonded to the pyrazole ring. Formula I thus encompasses enantiomersof formulae IIa and IIb:

wherein X, Ar, R¹ and R² are as defined previously,and also enantiomers of formulae IIIa and IIIb:

wherein X, Ar, R¹ and R² are as defined previously.

It will also be apparent that when X represents H formula IIa isidentical to formula IIIa and formula IIb is identical to formula IIIb.

It is to be emphasised that the invention, for each compound inaccordance with formula I, encompasses both enantiomeric forms, eitheras homochiral compounds or as mixtures of enantiomers in any proportion.

In a preferred embodiment of the invention, the compound of formula I isa homochiral compound of formula IIa or formula IIIa, or apharmaceutically acceptable salt thereof.

Where a variable occurs more than once in formula I or in a substituentthereof, the individual occurrences of that variable are independent ofeach other, unless otherwise specified.

As used herein, the expression “hydrocarbon group” refers to groupsconsisting solely of carbon and hydrogen atoms. Such groups may compriselinear, branched or cyclic structures, singly or in any combinationconsistent with the indicated maximum number of carbon atoms, and may besaturated or unsaturated, including aromatic when the indicated maximumnumber of carbon atoms so permits.

As used herein, the expression “C_(1-x)alkyl” where x is an integergreater than 1 refers to straight-chained and branched alkyl groupswherein the number of constituent carbon atoms is in the range 1 to x.Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl andt-butyl. Derived expressions such as “C₂₋₆alkenyl”, “hydroxyC₁₋₆alkyl”,“heteroarylC₁₋₆alkyl”, “C₂₋₆alkynyl” and “C₁₋₆alkoxy” are to beconstrued in an analogous manner. Most suitably, the number of carbonatoms in such groups is not more than 6.

The expression “C₃₋₆cycloalkyl” as used herein refers to nonaromaticmonocyclic hydrocarbon ring systems comprising from 3 to 6 ring atoms.Examples include cyclopropyl, cyclobutyl, cyclopentyl; cyclohexyl andcyclohexenyl.

The expression “cycloalkylalkyl” as used herein includes groups such ascyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl andcyclohexylmethyl.

The term “halogen” as used herein includes fluorine, chlorine, bromineand iodine, of which fluorine and chlorine are preferred.

For use in medicine, the compounds of formula I may be in the form ofpharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds of formula I or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundaccording to the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, sulfuric acid,methanesulfonic acid, benzenesulfonic acid, fumaric acid, maleic acid,succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid,tartaric acid, carbonic acid or phosphoric acid. Alternatively, wherethe compound of the invention carries an acidic moiety, apharmaceutically acceptable salt may be formed by neutralisation of saidacidic moiety with a suitable base. Examples of pharmaceuticallyacceptable salts thus formed include alkali metal salts such as sodiumor potassium salts; ammonium salts; alkaline earth metal salts such ascalcium or magnesium salts; and salts formed with suitable organicbases, such as amine salts (including pyridinium salts) and quaternaryammonium salts.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

In the compounds of formula I, X preferably represents H, OH or F, morepreferably H or F. In one particular embodiment, X is H. In anotherparticular embodiment, X is F.

Ar represents phenyl or 6-membered heteroaryl, either of which bears 0-3substituents independently selected from halogen, CF₃, CHF₂, CH₂F, NO₂,CN, OCF₃, C₁₋₆alkyl and C₁₋₆-alkoxy. Examples of suitable 6-memberedheteroaryl groups represented by Ar include pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl and triazinyl, of which pyridyl is a preferredexample. Preferably, the phenyl or heteroaryl ring bears 0 to 2substituents. Preferred substituents include halogen (especiallychlorine and fluorine), CN, C₁₋₆alkyl (especially methyl), C₁₋₆alkoxy(especially methoxy), OCF₃ and CF₃. If two or more substituents arepresent, preferably not more than one of them is other than halogen oralkyl. Examples of groups represented by Ar include phenyl,monohalophenyl, dihalophenyl, trihalophenyl, cyanophenyl, methylphenyl,methoxyphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, pyridyl,monohalopyridyl and trifluoromethylpyridyl, wherein “halo” refers tofluoro or chloro. Suitable specific values for Ar include2-fluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl,4-chlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl,3,4-difluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl,3,4,5-trifluorophenyl, 4-cyanophenyl, 4-methylphenyl, 4-methoxyphenyl,2-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl,4-(trifluoromethoxy)phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,pyrazin-2-yl, 5-methylpyridin-2-yl, 5-fluoropyridin-2-yl,5-chloropyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl and6-(trifluoromethyl)pyridin-3-yl. Preferred examples include2-fluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl,4-chlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl,3,4-difluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl,4-(trifluoromethyl)phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.

In a particularly preferred embodiment, Ar represents 4-fluorophenyl.

R¹ represents a hydrocarbon group of 1-5 carbon atoms which isoptionally substituted with up to 3 halogen atoms, and thus may comprisecyclic or acyclic hydrocarbon residues or combinations thereof,saturated or unsaturated, up to a maximum of 5 carbon atoms in total.The hydrocarbon group represented by R¹ is preferably unsubstituted oris substituted with up to 3 fluorine atoms Examples include methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl,cyclopropylmethyl and allyl. Preferred examples include methyl, ethyland 2,2,2-trifluoroethyl. Most preferably, R¹ represents methyl.

R² represents H or a hydrocarbon group of 1-10 carbon atoms which isoptionally substituted with up to 7 halogen atoms, with the proviso thatwhen X is H, R² does not represent 2,2,2-trifluoroethyl. Suitablehydrocarbon groups represented by R² include alkyl, cycloalkyl,cycloalkylalkyl, alkenyl and benzyl groups optionally bearing up to 7,preferably up to 5, and most preferably up to 3 halogen substituents,the preferred halogen substituent being fluorine or chlorine, especiallyfluorine. Said alkyl, cycloalkyl, cycloalkylalkyl and alkenyl groupstypically comprise up to 6 carbon atoms. Examples of groups representedby R² include H, benzyl, n-propyl, 2,2-dimethylpropyl, n-butyl,isopropyl, t-butyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl,2,2,3,3,3-pentafluoropropyl, 3,3,3-trifluoropropyl, allyl, cyclopropyl,cyclobutyl and cyclopropylmethyl.

Examples of compounds in accordance with the invention include compoundsof formula IIa or formula IIIa in which Ar is 4-fluorophenyl, R¹ ismethyl and X and R² are as indicated in the following table: Formula(IIa or IIIa) X R² IIa F 2,2,2-trifluoroethyl IIIa F2,2,2-trifluoroethyl IIa OH 2,2,2-trifluoroethyl * H allyl * Hn-propyl * H 2,2-dimethylpropyl * H cyclobutyl * H benzyl * H n-butyl *H cyclopropylmethyl * H 3,3,3-trifluoropropyl * H isopropyl * Ht-butyl * H cyclopropyl * H 2,2,3,3,3-pentafluoropropyl * H2,2-difluoroethyl* - when X is H, formulae IIa and IIIa are identical.

The compounds of the present invention have an activity as inhibitors ofγ secretase.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention and a pharmaceutically acceptablecarrier. Preferably these compositions are in unit dosage forms such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, transdermal patches, auto-injector devices or suppositories;for oral, parenteral, intranasal, sublingual or rectal administration,or for administration by inhalation or insufflation. The principalactive ingredient typically is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate and dicalciumphosphate, or gums, dispersing agents, suspending agents or surfactantssuch as sorbitan monooleate and polyethylene glycol, and otherpharmaceutical diluents, e.g. water, to form a homogeneouspreformulation composition containing a compound of the presentinvention, or a pharmaceutically acceptable salt thereof. When referringto these preformulation compositions as homogeneous, it is meant thatthe active ingredient is dispersed evenly throughout the composition sothat the composition may be readily subdivided into equally effectiveunit dosage forms such as tablets, pills and capsules. Thispreformulation composition is then subdivided into unit dosage forms ofthe type described above containing from 0.1 to about 500 mg of theactive ingredient of the present invention. Typical unit dosage formscontain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, ofthe active ingredient. Tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, liquid- or gel-filled capsules, suitablyflavoured syrups, aqueous or oil suspensions, and flavoured emulsionswith edible oils such as cottonseed oil, sesame oil, or coconut oil, aswell as elixirs and similar pharmaceutical vehicles. Suitable dispersingor suspending agents for aqueous suspensions include synthetic andnatural gums such as tragacanth, acacia, alginate, dextran, sodiumcarboxymethylcellulose, methylcellulose, poly(ethylene glycol),poly(vinylpyrrolidone) or gelatin.

The present invention also provides a compound of the invention or apharmaceutically acceptable salt thereof for use in a method oftreatment of the human body. Preferably the treatment is for a conditionassociated with the deposition of β-amyloid. Preferably the condition isa neurological disease having associated β-amyloid deposition such asAlzheimer's disease.

The present invention further provides the use of a compound of thepresent invention or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for treating or preventing Alzheimer'sdisease.

Also disclosed is a method of treatment of a subject suffering from orprone to Alzheimer's disease which comprises administering to thatsubject an effective amount of a compound according to the presentinvention or a pharmaceutically acceptable salt thereof.

For treating or preventing Alzheimer's Disease, a suitable dosage levelis about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kgper day, more preferably about 0.05 to 50 mg/kg of body weight per day,and for the most preferred compounds, about 0.1 to 10 mg/kg of bodyweight per day. The compounds maybe administered on a regimen of 1 to 4times per day. In some cases, however, a dosage outside these limits maybe used.

Compounds of formula I in which R² is other than H may be prepared byreaction of an aziridine derivative (1) with R^(2a)NH₂:

wherein the pyrazole group is attached at one of the positions indicatedby an asterisk and X is attached at a position adjacent thereto, R^(2a)is R² that is other than H, and X, Ar, R¹ and R² have the same meaningsas before. The reaction may be carried out by heating the reagents at100° C. in DMSO in a sealed tube for 16 hours.

Corresponding compounds wherein R² is H may be prepared by reacting anaziridine (1) with p-methoxybenzylamine in the manner described above,and treating the product with trifluoroacetic acid at ambienttemperature to remove the p-methoxybenzyl group.

The aziridines (1) may be prepared by reaction of imines (2) withtrimethylsulfoxonium iodide in the presence of sodium hydride:

where X, Ar and R¹ have the same meanings as before. The reaction takesplace in DMSO at ambient temperature.

The imines (2) may be prepared by condensation of ketones (3) withMe₂NSO₂NH₂:

where X, Ar and R¹ have the same meanings as before. The reaction may becarried out by refluxing the reagents in THF in the presence of titanium(IV) ethoxide for 16 hours.

The ketones (3) may be prepared by coupling of boronates (4) withpyrazole derivatives (5):

wherein R³ represents H or C₁₋₆alkyl, or the two OR³ groups complete acyclic boronate ester such as the pinacolate, L represents a leavinggroup such as triflate, bromide or iodide (preferably triflate), and X,Ar and R¹ have the same meanings as before. The coupling takes place inthe presence of a Pd catalyst such astetrakis(triphenylphosphine)palladium(0), typically in the presence ofan inorganic base such as potassium acetate or potassium carbonate inDMF at 100° C.

Boronates (4) may be prepared by reaction of triflates (6) with asuitable boron reagent, such as bis(pinacolato)diboron:

wherein Tf represents trifluoromethanesulfonyl and X has the samemeaning as before. The reaction takes place under similar conditions asthe coupling of (4) and (5), although the preferred catalyst is[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

Triflates (6) are prepared from phenols (7) by reaction with triflicanhydride:

where and X has the same meaning as before. The reaction takes place indichloromethane solution at 0° C. in the presence of a base such aspyridine.

The phenols (7) in which X is H are known in the literature (J. Org,Chem. 1982, 47, 4329), and the other compounds of formula (7) may beprepared analogously, or by suitable manipulation (e.g. halogenation) of(7) (X═H).

Pyrazoles (5) in which L is triflate are accessible from the reaction ofalkynes Ar—C≡C—CO₂Me with R¹NHNH₂ and treatment of the resultingpyrazolones with triflic anhydride. Pyrazoles (5) in which L is Br areavailable by reaction of nonaflates (8) with ArZnBr:

where Nf represents nonafluorobutanesulfonyl, and Ar and R¹ have thesame meaning as before.

In an alternative route to the compounds of formula I, triflates (9a)are coupled with pyrazole stannanes (10):

where X, Ar, R¹, R², R³ and Tf have the same meanings as before. Thecoupling takes place in the presence of a Pd catalyst such astetrakis(triphenylphosphine)palladium(0), in the presence lithiumchloride in dioxan at 100° C.

Triflates (9a) may be prepared by conversion of the ketone group of (7)to a cyclic sulfamide moiety by the process described above, andtreatment of the phenolic product with triflic anhydride. Stannanederivatives (10) may be prepared as described for Intermediate D in theExamples herein.

Alternatively, triflates (9a) may be converted to boronates (9b) andcoupled with pyrazoles (5).

The phenol precursors of triflates (9a) in which X is H are amenable tochemical manipulation (e.g. fluorination) to provide correspondingcompounds in which X is other than H. Alternatively, said phenols may beiodinated to provide the corresponding ortho-iodophenols, which may betransformed into boronates (9b) (X═OH) and coupled with pyrazoles (5) toprovide compounds of formula I in which X is OH.

It will also be appreciated that where more than one isomer can beobtained from a reaction then the resulting mixture of isomers can beseparated by conventional means.

Where the above-described process for the preparation of the compoundsaccording to the invention gives rise to mixtures of stereoisomers,these isomers may be separated by conventional techniques such aspreparative chromatography. The novel compounds may be prepared inracemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The novel compounds may, forexample, be resolved into their component enantiomers by standardtechniques such as preparative HPLC, or the formation of diastereomericpairs by salt formation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary. Alternatively, such techniques maybe carried out on racemic synthetic precursors of the compounds ofinterest.

In a preferred route to enantiomerically pure compounds of formula I,racemic intermediates (7) are subjected to preparative chiral HPLC toprovide the corresponding homochiral intermediates, which are thenconverted to homochiral compounds of formula I by the routes indicatedabove.

Where they are not commercially available, the starting materials andreagents used in the above-described synthetic schemes may be preparedby conventional means.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups maybe removed at a convenientsubsequent stage using methods known from the art.

An assay which can be used to determine the level of activity ofcompounds of the present invention is described in WO01/70677. Apreferred assay to determine such activity is as follows:

-   1) SH-SY5Y cells stably overexpressing the βAPP C-terminal fragment    SPA4CT, are cultured at 50-70% confluency. 10 mM sodium butyrate is    added 4 hours prior to plating.-   2) Cells are plated in 96-well plates at 35,000 cells/well/100 μL in    Dulbeccos minimal essential medium (DMEM) (phenol red-free)+10%    foetal bovine serum (FBS), 50 mM HEPES buffer (pH 7.3), 1%    glutamine.-   3) Make dilutions of the compound plate. Dilute stock solution 18.2×    to 5.5% DMSO and 11× final compound concentration. Mix compounds    vigorously and store at 4° C. until use.-   4) Add 10 μL compound/well, gently mix and leave for 18 h at 37° C.,    5% CO₂.-   5) Prepare reagents necessary to determine amyloid peptide levels,    for example by Homogeneous Time Resolved Fluorescence (HTRF) assay.-   6) Plate 160 μL aliquots of HTRF reagent mixture to each well of a    black 96-well HTRF plate.-   7) Transfer 40 μL conditioned supernatant from cell plate to HTRF    plate. Mix and store at 4° C. for 18 hours.-   8) To determine if compounds are cytotoxic following compound    administration, cell viability is assessed by the use of redox dye    reduction. A typical example is a combination of redox dye MTS    (Promega) and the electron coupling reagent PES. This mixture is    made up according to the manufacturer's instructions and left at    room temperature.-   9) Add 10 μL/well MTS/PES solution to the cells; mix and leave at    37° C.-   10) Read plate when the absorbance values are approximately 0.4-0.8.    (Mix briefly before reading to disperse the reduced formazan    product). 11) Quantitate amyloid beta 40 peptide using an HTRF plate    reader.

Alternative assays are described in Biochemistry, 2000, 39(30),8698-8704.

See also, J. Neuroscience Methods, 2000, 102, 61-68.

The compounds of the present invention show unexpectedly high affinitiesas measured by the above assays. Thus the following Examples all had anED₅₀ of less than 100 nM, typically less than 10 nM, and frequently lessthan 1 nM in at least one of the above assays. In general, the compoundsalso exhibit good oral bioavailability and/or brain penetration.

The following examples illustrate the present invention.

EXAMPLES

To a solution of methyl 4-(fluorophenyl)propynoate (J. Org. Chem. 1987,52(16), 3662-8) (13 g, 73 mmol) in methanol (60 ml) was added water (60ml) followed by methylhydrazine (4 ml, 77 mmol), the mixture was stirredfor 6 hrs at 60° C. then left to stand overnight. The solid was filteredand washed with water then a minimum volume of methanol and driedovernight, affording 7.7 g of5-(4-fluorophenyl)-1-methyl-1,2-dihydropyrazol-3-one (55%). δ (¹H, 500MHz, CDCl₃) 3.68 (3H, s), 5.68 (1H, s), 7.13-7.17 (2H, m), 7.37-7.40(2H, m).

To a cooled suspension of the above pyrazolone (15.5 g, 81 mmol) in drypyridine (100 ml) was added in three portions trifluoromethanesulfonicanhydride (24 g, 85 mmol) maintaining the temperature below 5° C. Thecooling bath was then removed and the reaction was stirred for two hoursbefore pouring into 2M hydrochloric acid and extracting into ethylacetate. The organic layer was washed with brine, saturated sodiumhydrogen carbonate, and dried (sodium sulfate), filtered and evaporatedto yield a residue which was dissolved in toluene and evaporated andthen dissolved in isohexane and filtered through a plug of silica,eluting with dichloromethane. The solvent was evaporated to yieldproduct as a colourless oil (23.4 g, 89%) δ (¹H, 500 MHz, CDCl₃) 3.80(3H, s), 6.14 (1H, s), 7.15-7.19 (2H, m), 7.38-7.42 (2H, m).

Step 1

Racemic2-hydroxy-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[α][8]annulen-11-one(J. Org. Chem, 1982, 47, 4329) was resolved using a Berger SFCsemi-preparative instrument (chiralpak AS (25×2 cm, 20 um); 15%MeOH/CO₂@ 50 mL/min; 35° C.; 100 bar), retaining the second elutedenantiomer.

To a stirred solution of the homochiral phenol (6.83 g, 34 mmol) in dryDCM (40 mL) at 0° C. under nitrogen was added pyridine (3.8 mL, 47 mmol)followed by triflic anhydride (8.0 mL, 47 mmol). The reaction wasstirred at 0° C. for 2 hours, water (40 mL) added, the layers separated,and the aqueous layer extracted with DCM (×2). The combined extractswere washed with brine (×1), dried (MgSO₄), filtered and evaporated. Theresidue was purified by chromatography on silica, eluting with 10-15%EtOAc/hexane, to give the triflate (9.64 g, 85%). (400 MHz ¹H, δ-CDCl₃)1.28 (2H, m), 1.92 (2H, m), 2.64 (2H, m), 2.85-3.05 (4H, m), 7.13 (2H,m), 7.29 (1h, m).Step 2

A solution of the triflate from Step 1 (9.64 g, 29 mmol),1,1′-bis(diphenylphosphino)ferrocene (1.60 g, 2.8 mmol),bis(pinacolato)diboron (8.05 g, 32 mmol) and KOAc (8.49 g, 86 mmol) indry DMF (200 mL) was deoxygenated by bubbling nitrogen through thesolution for 20 minutes. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride (2.354 g, 2.9 mmol) was added and deoxygenation wascontinued for a further 10 minutes. The reaction was heated at 100° C.for 4 hours, then allowed to cool and diluted with water (400 mL). Thecatalyst was removed by filtration through Hyflo® and the filtrate wasextracted with EtOAc (×3). The combined extracts were washed with waterthen brine, dried (MgSO₄), filtered and evaporated. The residue waspurified by chromatography on silica, eluting with 10-20% EtOAc/hexaneto give the product (7.39 g, 82%). (360 MHz ¹H, δ-CDCl₃) 1.29 (2H, m),1.35 (12H, s), 1.85 (2H, m), 2.59 (2H, m), 2.84-3.01 (4H, m), 7.21 (1H,m), 7.63 (2H, m).Step 3

A solution of the boronate from Step 2 (2.06 g, 6.6 mmol), IntermediateA (1.95 g, 6.0 mmol), and sodium carbonate (0.70 g, 6.6 mmol) in dry DMF(30 mL) was deoxygenated by bubbling nitrogen through the solution for30 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.52 g, 0.45mmol) was added and deoxygenation was continued for a further 10minutes. The reaction was heated at 100° C. for 16 hours then allowed tocool and diluted with water (40 mL). The catalyst was removed byfiltration through Hyflo® and the filtrate was extracted with EtOAc(×3). The combined extracts were washed with water then brine, dried(MgSO₄), filtered and evaporated. The residue was purified bychromatography on silica, eluting with 10-40% EtOAc/hexane to give theproduct (1.52 g, 64%). (400 MHz ¹H, δ-CDCl₃) 1.37 (2H, m), 1.87 (2H, m),2.61 (2H, m), 2.89-3.09 (4H, m), 3.91 (3H, s), 6.58 (1H, s), 7.15-7.26(3H, m), 7.44 (2H, m), 7.61 (1H, m), 7.71 (1H, m). MS (ES+) 361, MH⁺.Step 4

A solution of the ketone from Step 3 (0.360 g, 1.0 mmol),N,N-dimethylsulfamide (0.620 g, 5.0 mmol) and titanium (IV) ethoxide(tech., 0.63 mL, 3.0 mmol) in dry THF (5 mL) was stirred and heated atreflux under nitrogen for 16 hours. The reaction was allowed to cool toroom temperature, poured into rapidly stirred brine (60 mL), stirred for1 hour, then filtered through Hyflo®, washing with EtOAc. The layers ofthe filtrate were separated, and the aqueous layer was extracted withEtOAc. The combined organic extracts were washed with brine, dried(MgSO₄), filtered and evaporated. The residue was purified bychromatography on silica, eluting with 5-20% EtOAc/DCM, to give theimine (0.383 g, 82%). MS (ES+) 467, MH⁺.Step 5

Sodium hydride (60% dispersion in oil, 0.223 g, 5.7 mmol) was addedportionwise to a stirred suspension of trimethyl sulfoxonium iodide(1.261 g, 5.7 mmol) in dry DMSO (10 mL) at room temperature undernitrogen. After 1 hour at room temperature, a solution of the imine fromStep 4 (1.783 g, 3.8 mmol) in dry DMSO (15 mL) was added such that theinternal temperature remained below 30° C. The mixture was stirred atroom temperature for 2 hours, then quenched with water (40 mL). Thereaction was extracted with EtOAc and the combined organic extractswashed with water then brine, dried (MgSO₄), filtered and evaporated.The residue was purified by chromatography on silica, eluting with20-50% EtOAc/hexane, to give the aziridine (1.544 g, 84%). (360 MHz ¹H,δ-CDCl₃) 1.30 (2H, m), 1.73 (2H, m), 2.24 (2H, m), 2.44 (2H, m), 2.80(2H, m), 2.97 (6H, s), 3.59 (2H, m), 3.90 (3H, s), 6.56 (1H, s), 7.15(3H, m), 7.43 (2H, m), 7.52 (1H, m), 7.58 (1H, m). MS (ES+) 481, MH⁺.

Prepared as described in WO 02/36555, Example 83, starting fromhomochiral2-hydroxy-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[a][8]annulen-11-one,obtained as described in Step 1 of the above Intermediate B preparation.

Step 1

Methylamine (2.0M in methanol, 6 ml, 12 mmol) was added to a stirredsolution of (±)-bromo(4-fluorophenyl)acetic acid (1.5 g, 6.4 mmol) inmethanol (4 ml) at 0° C. The cooling bath was removed and the reactionwas stirred at room temperature for 3 hours. The reaction mixture wasevaporated and the residue was crystallised (methanol/water) to give theamino acid (795 mg, 67% in two batches) as a colourless solid. (400 MHz¹H, δ-D₂O) 2.61 (3H, s), 4.62 (1H, s), 7.24 (2H, t, J=8.8 Hz), 7.46-7.49(2H, m).Step 2

Sodium nitrite (250 mg, 3.6 mmol) was added portionwise to a stirredsuspension of the amino acid from Step 1 (325 mg, 1.8 mmol) in water (1ml) and concentrated hydrochloric acid (0.3 ml) at 0° C. After 1 hourdiethylether (1 ml) was added, then after an additional 5 hours at 0°C., water (5 ml) was added and the mixture was extracted withdichloromethane (×4). The combined extracts were dried (Na₂SO₄),filtered and evaporated to give(±)-(4-fluorophenyl)(1-methyl-2-oxohydrazino)acetic acid (320 mg, 84%)as an oil. (400 MHz ¹H, δ-CDCl₃, 1.5:1 mixture of isomers) 2.95 (1.8H,s), 3.59 (1.2H, s), 6.20 (0.4H, s), 6.71 (0.6H, s), 7.12-7.17 (2H, m),7.28-7.31 (0.9H, m), 7.37-7.40 (1.1H, m), 8.3 (1H, br s).

Step 3

4-(4-fluorophenyl)-3-methyl-1,2,3-oxadiazol-3-ium-5-olate

Trifluoroacetic anhydride (225 μl, 1.6 mmol) was added to a stirredsolution of the product of Step 2 (320 mg, 1.5 mmol) in dry diethylether (15 ml) at 0° C. under nitrogen. After 3 hours the precipitate wascollected by filtration to give the title compound (124 mg, 43%) as acolourless solid. A further sample (50 mg, 17%) was obtained byevaporation of the filtrate and purification of the residue bychromatography on silica, eluting with 1:1 ethyl acetate/hexanes. (360MHz ¹H, δ-CDCl₃) 4.12 (3H, s), 7.20 (2H, t, J=8.6 Hz), 7.55-7.59 (2H,m).

Step 4

5-(4-fluorophenyl)-1-methyl-3-(tributylstannyl)-1H-pyrazole

A solution of the product from Step 3 (120 mg, 0.62 mmol) andethynyltributyltin (360 μl, 1.2 mmol) in m-xylene (750 μl) was heated at140° C. under nitrogen for 36 hours. The reaction mixture diluted withtoluene and loaded directly onto a silica column. Elution with 5 to 8%ethyl acetate/hexanes gave the title compound (63 mg, 22%) as an oil.(400 MHz ¹H, δ-CDCl₃) 0.90 (9H, t, J=7.3 Hz), 1.08-1.12 (6H, m)1.30-1.39 (6H, m), 1.56-1.61 (6H, m), 3.90 (3H, s), 6.33 (1H, s),7.11-7.15 (2H, m), 7.36-7.40 (2H, m).

Example 1

A solution of Intermediate B (96 mg, 0.2 mmol) and allylamine (114 mg,2.0 mmol) in DMSO (2 mL) was stirred and heated at 100° C. in a sealedtube for 16 hours. After cooling, water (10 mL) was added, the reactionwas extracted with EtOAc, and the combined organic extracts were washedwith brine, dried (MgSO₄), filtered and evaporated. The residue waspurified by chromatography on silica, eluting with 20-30% EtOAc/hexane,to give the title compound (82 mg, 84%). (360 MHz ¹H, δ-CDCl₃) 1.35 (2H,m), 1.68 (2H, m), 2.42 (2H, m), 2.74 (2H, m), 3.19 (4H, m), 3.69 (2H, d,J=6.4 Hz), 3.90 (3H, s), 4.68 (1H, s), 5.28 (1H, d, J=10.3 Hz), 5.34(1H, d, J=16.6 Hz), 5.90 (1H, m), 6.56 (1H, s), 7.15 (3H, m), 7.44 (2H,m), 7.52 (1H, m), 7.59 (1H, m). MS (ES+) 493, MH⁺.

Examples 2-13

The compounds in table 1 were prepared from Intermediate B by the methodof Example 1 substituting the appropriate amine for allylamine. TABLE 1

Example R m/z (M + H)⁺ 2 nPr 495 3

523 4

507 5 Bn 543 6 nBu 509 7

507 8

549 9

495 10

509 11

585 12

517 13

493

Example 14

The procedure of Example 1 was repeated, substitutingp-methoxybenzylamine for allylamine.

A solution of the resulting sulfamide (78 mg, 0.2 mmol) in TFA (2 mL)was stirred at room temperature for 3 hours. The reaction wasconcentrated in vacuo and saturated sodium bicarbonate solution (10 mL)was added. The mixture was extracted with DCM, the combined organicextracts were washed with brine, dried (MgSO₄), filtered and evaporated.The residue was purified by chromatography on silica, eluting with40-60% EtOAc/hexane, to give the desired product. (49 mg, 80%). (360 MHz1H, δ-CDCl₃) 1.37 (2H, m), 1.68 (2H, m), 2.42 (2H, m), 2.79 (2H, m),3.24 (2H, m), 3.38 (2H, d, J=7.4 Hz), 3.90 (3H, s), 4.56 (1H, t, J=7.2Hz), 4.60 (1H, s), 6.56 (1H, s), 7.16 (3H, m), 7.44 (2H, m), 7.53 (1H,m), 7.60 (1H, m). MS (ES+) 453, MH⁺.

Example 15

and

Example 16

Step 1

A mixture of Intermediate C (500 mg, 1.3 mmol) and N-fluoropyridiniumtriflate (500 mg, 2.0 mmol) in 1,2-dichloroethane (8 ml) was heated atreflux for 16 hours, then cooled to room temperature and concentrated invacuo. The residue was diluted with water (30 ml) and extracted withdichloromethane (3×20 ml). The organics were dried (MgSO₄) andevaporated in vacuo to give a red foam (495 mg). The foam was purifiedby chromatography on SiO₂ [1% ethyl acetate/dichloromethane] to give thefluorophenols as a mixture of regioisomers (272 mg, 53%). M/Z ES⁻ (393)(M-1)⁻.

A solution of the isomeric fluorophenols (202 mg, 0.51 mmol) in pyridine(5 ml) at 0° C., under a nitrogen atmosphere, was treated withtrifluoromethanesulfonic anhydride (170 μl, 1.0 mmol) and the mixturewas stirred at 0° C. for 2 hours. The reaction was diluted withhydrochloric acid (1N, 30 ml) and extracted with ethyl acetate (2×40ml). The organics were washed with brine, dried (MgSO₄) and evaporatedin vacuo to a gummy foam (254 mg). The foam was purified bychromatography on SiO₂ [15% ethyl acetate/isohexane] to give thetriflates as a mixture of regioisomers (173 mg, 65%). M/Z ES⁺(527)(MH)⁺.

Step 2

A mixture of the triflates from Step 1 (97 mg, 0.18 mmol), IntermediateD (86 mg, 0.18 mmol) and lithium chloride (23 mg, 0.54 mmol) in dioxane(2 ml) was degassed by a stream of nitrogen for 10 minutes.Tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) was addedand following a further 10 minutes of degassing the reaction was stirredat 100° C. for two and a half hours. After cooling to room temperature,more tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) wasadded, the reaction was degassed for 10 minutes, then heated at 100° C.for 16 hours. The reaction was diluted with sodium bicarbonate (sat, 15ml) and ethyl acetate (20 ml) and the mixture was filtered through a bedof Hyflo®. The phases were separated and the aqueous extracted withethyl acetate (20 ml) The organics were washed with brine, dried (MgSO₄)and evaporated in vacuo to an orange/brown foam which was purified bychromatography on SiO₂ [ethyl acetate/isohexane 1:2] to give Example 12,less polar on SiO₂, as a white foam (23 mg, 23%) M/Z ES+(553) (MH)⁺ andExample 13, more polar on SiO₂, as a white foam (52 mg, 52%) M/ZES+(553) (MH)⁺.

Example 17

Step 1

The enantiomer of Intermediate C was prepared by the same method asIntermediate C, starting with the first-eluted enantiomer obtained fromthe resolution described in Step 1 of the preparation of Intermediate B.

Aqueous sodium hypochlorite (4%, 25 g) was added dropwise to a cold (0°C.) solution of the enantiomer of Intermediate C (5.0 g, 13.3 mmol),sodium iodide (2.0 g, 13.3 mmol) and sodium hydroxide (532 mg, 13.3mmol) in methanol (200 ml). The mixture was stirred at 0° C. for 2hours, then treated with sodium thiosulfate (10% w/v, 200 ml),neutralised (1N HCl) and concentrated in vacuo. The residue wasextracted with ethyl acetate (4×200 ml), and the organics washed withbrine, dried (MgSO4) and evaporated in vacuo to a yellowish solid (7.25g) which was purified by chromatography on SiO₂ [5% ethylacetate/dichloromethane] to give the desired iodide as a white foam (5.4g, 81%) M/Z ES⁻ (501) (M−H)⁻.Step 2

A mixture of iodophenol from Step 1 (502 mg, 1 mmol), pinacolborane (540μl, 3.7 mmol) and triethylamine (0.45 ml, 3.2 mmol) in dioxane wasdegassed via a stream of nitrogen,[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)dichloromethane adduct (27 mg, 0.04 mmol) was added, and following afurther period of degassing the reaction was heated at 80° C. for 16hours. Further triethylamine (0.45 ml, 3.2 mmol), pinacolborane (540 Tl,3.7 mmol) and Pd catalyst (27 mg, 0.04 mmol) were added, and following aperiod of degassing the reaction was heated at 80° C. for 24 hours. Thereaction was cooled to room temperature, diluted with ethyl acetate (30ml) and washed with HCl (1N, 3×15 ml). The organics were washed withbrine, dried (MgSO₄) and evaporated in vacuo to a brown gum (640 mg)which was purified by filtration through a plug of silica andtrituration with hot hexane to give a brown solid (345 mg, 69%) M/Z ES⁻(501) (M-1)⁻.Step 3

A mixture of the boronate from Step 2 (50 mg, 0.1 mmol), Intermediate A(32 mg, 0.1 mmol) and potassium phosphate (46 mg, 0.2 mmol) in DMF wasdegassed via a stream of nitrogen.Tetrakis(triphenylphosphine)palladium(0) (6 mg, 5.2 mmol) was added andfollowing a further degassing the reaction was heated at 100° C., undermicrowave irradiation, for 10 minutes. The reaction was diluted with HCl(1N, 10 ml) and extracted with diethylether (2×30 ml). The organics werewashed with water (2×30 ml) and brine, dried (MgSO₄) and evaporated invacuo to a brown gum (84 mg) which was purified by column chromatographyon silica [2% ethyl acetate/dichloromethane] to give a white solid (2.6mg, 5%) M/Z ES⁻ (551) (M-1)⁻.

1. A compound of formula I:

wherein the pyrazole group is attached at one of the positions indicated by an asterisk and X is attached at a position adjacent thereto; X represents H, OH, C₁₋₄alkoxy, Cl or F; Ar represents phenyl or 6-membered heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, C₁₋₆alkyl and C₁₋₆alkoxy; R¹ represents a hydrocarbon group of 1-5 carbon atoms which is optionally substituted with up to 3 halogen atoms; and R² represents H or a hydrocarbon group of 1-10 carbon atoms which is optionally substituted with up to 7 halogen atoms; provided that when X is H, R² does not represent 2,2,2-trifluoroethyl; or a pharmaceutically acceptable salt thereof.
 2. A compound according to claim 1 of formula IIa:

or formula IIIa: or a pharmaceutically acceptable salt thereof.
 3. A compound according to claim 1 wherein Ar represents phenyl, monohalophenyl, dihalophenyl, trihalophenyl, cyanophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, pyridyl, monohalopyridyl and trifluoromethylpyridyl, wherein “halo” refers to fluoro or chloro.
 4. A compound according to claim 1 wherein R² represents H, benzyl, or alkyl, alkenyl, cycloalkyl or cycloalkylalkyl of up to 6 carbon atoms, or benzyl, and optionally bears up to 5 fluorine substituents.
 5. A compound according to claim 2 wherein X is H, R¹ is methyl, Ar is 4-fluorophenyl and R² is selected from H, benzyl, n-propyl, 2,2-dimethylpropyl, n-butyl, isopropyl, t-butyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2,3,3,3-pentafluoropropyl, 3,3,3-trifluoropropyl, allyl, cyclopropyl, cyclobutyl and cyclopropylmethyl.
 6. The compound of formula:

or a pharmaceutically acceptable salt thereof.
 7. A pharmacuetical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 8-9. (canceled)
 10. A method of treatment of a subject suffering from or prone to Alzheimer's disease which comprises administering to that subject an effective amount of a compound according to claim
 1. 11. A process for preparing a compound according to claim 1 in which R² is other than H comprising reaction of a compound of formula (1):

with R^(2a)NH₂; where the pyrazole group is attached at one of the positions indicated by an asterisk and X is attached at a position adjacent thereto; R^(2a) is R² that is other than H; and X and Ar, R¹ and R² are as defined in claim
 1. 